Uveitis is a group of sight-threatening intraocular inflammatory diseases that includes Behet's disease, birdshot retinochoroidopathy, Vogt-Koyanagi-Harada's, sympathetic ophthalmia, ocular sarcoidosis. Studies of experimental autoimmune uveoretinitis (EAU), the model of uveitis led to the conclusion that Th1 cells are the etiologic agent of uveitis because IFN-gamma levels are elevated in the retina during uveitis and IL12p40 is required for EAU induction. However, subsequent studies revealed that IL-12 down-regulates EAU and treatment of mice with EAU with anti-IFN-gamma antibodies was found to exacerbate the disease, casting doubts on the role of this T cell subset as the etiologic agent of uveitis. Recent reports implicating Th17 cells in pathogenesis of human uveitis and scleritis has further complicated our understanding of the role of different T cell subsets in uveitis. Besides Th1 and Th17 cells, Th2 and Treg are also detected in the eye during uveitis and exact roles of these T cell subtypes in the immunopathogenic process are largely unknown. Thus in context of treating uveitis, it is important to note that presence of T cells in the retina compromises vision and preventing entry of all T cell types or limiting their expansion in the eye is of utmost importance. Accordingly, identifying molecular pathways amendable to therapeutic targeting has attracted attention as a potential strategy for limiting expansion of uveitogenic T cells in the eye. Recent reports indicating requirement of STAT3 for commitment of naive T cells towards the Th17 developmental pathway, suggest a potential involvement of STAT3 pathway in mediating CNS inflammatory diseases. In this study, we have generated mice with targeted deletion of STAT3 in the CD4+ T cell compartment (CD4Stat3-/-) and used them to examine whether STAT3 pathways are required for development of EAU, as well as, experimental autoimmune encephalomyelitis (EAE), another CNS disease that shares essential immunopathologic features as EAU. Here, we have shown that unlike the partial protection conferred by IL-17 blockage with IL-17 Abs, CD4stat3-/- mice are completely resistant to EAU or EAE and this dramatic outcome derives from combinatory mechanisms that include: IL-17 blockade;altered T cell homeostasis that favor expansion of anti-inflammatory responses;inhibition of T cell entry to CNS tissues. Resistance of STAT3 conditional knockout mice to development of EAE and EAU suggest that the STAT3 pathway is a potential therapeutic target for modulating these CNS inflammatory diseases.